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ETV2/ER71 Regulates the Generation of FLK1(+) Cells from Mouse

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ETV2/ER71 Regulates the Generation of FLK1(+) Cells from Mouse ETV2/ER71 regulates the generation of FLK1(+) cells from mouse embryonic stem cells through miR-126-MAPK signaling JY Kim, Emory University DH Lee, Emory University JK Kim, Emory University HS Choi, Emory University Bhakti Dwivedi, Emory University M Rupji, Emory University Jeanne Kowalski, Emory University H Song, Emory University JY Chang, Emory University Changwon Park, Emory University Journal Title: Stem Cell Research and Therapy Volume: Volume 10, Number 1 Publisher: BMC | 2019-11-19, Pages 328-328 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.1186/s13287-019-1466-8 Permanent URL: https://pid.emory.edu/ark:/25593/vh4ms Final published version: http://dx.doi.org/10.1186/s13287-019-1466-8 Copyright information: © 2019 The Author(s). This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). Accessed September 26, 2021 9:42 PM EDT Kim et al. Stem Cell Research & Therapy (2019) 10:328 https://doi.org/10.1186/s13287-019-1466-8 SHORT REPORT Open Access ETV2/ER71 regulates the generation of FLK1+ cells from mouse embryonic stem cells through miR-126-MAPK signaling Ju Young Kim1,2,3, Dong Hun Lee1,2, Joo Kyung Kim1,2, Hong Seo Choi1, Bhakti Dwivedi5, Manali Rupji5, Jeanne Kowalski5,6,7, Stefan J. Green8, Heesang Song1,9, Won Jong Park1, Ji Young Chang1, Tae Min Kim10 and Changwon Park1,2,3,4* Abstract Previous studies including ours have demonstrated a critical function of the transcription factor ETV2 (ets variant 2; also known as ER71) in determining the fate of cardiovascular lineage development. However, the underlying mechanisms of ETV2 function remain largely unknown. In this study, we demonstrated the novel function of the miR (micro RNA)-126-MAPK (mitogen-activated protein kinase) pathway in ETV2-mediated FLK1 (fetal liver kinase 1; also known as VEGFR2)+ cell generation from the mouse embryonic stem cells (mESCs). By performing a series of experiments including miRNA sequencing and ChIP (chromatin immunoprecipitation)-PCR, we found that miR-126 is directly induced by ETV2. Further, we identified that miR-126 can positively regulate the generation of FLK1+ cells by activating the MAPK pathway through targeting SPRED1 (sprouty-related EVH1 domain containing 1). Further, we showed evidence that JUN/FOS activate the enhancer region of FLK1 through AP1 (activator protein 1) binding sequences. Our findings provide insight into the novel molecular mechanisms of ETV2 function in regulating cardiovascular lineage development from mESCs. Keywords: ETV2/ER71, FLK1+ cells, miR-126, EGFL7, Embryonic stem cells Introduction compartments [5, 6]. We also showed that ETV2 can dir- The ETS (E26 transformation-specific or E-twenty-six ectly bind the promoters/enhancers of endothelial and specific sequence) transcription factor family members hematopoietic genes including Flk1 (fetal liver kinase 1; play key roles in diverse biological events including cell also known as VEGFR2) [5–7]. Together with the findings survival, cancer, vascular-angiogenesis and hematopoiesis that ETV2 can induce de novo generation of FLK1+ cells, mainly through the interaction between their conserved the multipotent progenitor for blood, endothelial and car- ETS DNA binding domain and the consensus sequence diac lineages from mouse embryonic stem cells (mESCs) (5′-GGAA/T-3′) present in the regulatory elements of [5], these results strongly suggest the critical function of their target genes [1, 2]. ETV2 (ets variant 2; also known ETV2 for the establishment of the cardiovascular system. as ER71), a member of the ETS transcription factor family, Reports from other groups further support the importance has been reported as an indispensable factor in establish- of ETV2 in this process [8–11]. Regarding the regulatory ing the cardiovascular system [3, 4]. We previously dem- mechanisms of ETV2 functions, several studies examining onstrated that deficiency in Etv2 led to embryonic lethality the ETV2 binding proteins have been reported. For ex- due to a complete lack of both vascular and hematopoietic ample, it was shown that the interaction between ETV2 and FOXC2 (forkhead box protein C2) plays an important role in regulating several key genes of the endothelial and * Correspondence: [email protected] 1Department of Pediatrics, Emory University School of Medicine, 2015 hematopoietic lineages [12, 13]. Also, our recent study re- Uppergate Dr. Atlanta, Atlanta, GA 30322, USA vealed the functional significance of the ETV2-OVOL2 2 Children’s Heart Research & Outcomes (HeRO) Center, Children’s Healthcare (ovo-like zinc finger 2) interaction in generating FLK1+ of Atlanta & Emory University, Atlanta, GA, USA Full list of author information is available at the end of the article cells and its further differentiation into the hematopoietic © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kim et al. Stem Cell Research & Therapy (2019) 10:328 Page 2 of 9 and endothelial cells [14]. However, the detailed molecular ETV2 ESCs upon Dox treatment (Figs. 1e and 2a). Next, insight into the ETV2 function remains largely unknown. we examined whether ETV2 can directly activate the To better understand the machinery of ETV2 that promoter of Egfl7, thus inducing the expression of miR- regulates the FLK1+ cell generation from mESCs, we 126. From the literature search and our own investiga- profiled miRNAs (micro RNAs) that are differentially tion, we found the highly conserved upstream region of regulated by ETV2 and found miR-126 as one of the the transcription start site in mouse and human EGFL7 direct downstream players of ETV2. We subsequently that contains two conserved potential ETS binding sites investigated the molecular mechanism of the miR-126/ (Fig. 2b). By performing the promoter assay, we revealed MAPK (mitogen-activated protein kinase) pathway in that the overexpression of Etv2 significantly increased ETV2-mediated FLK1+ cell generation. the activity of the Egfl7 promoter. However, the Egfl7 promoter construct with mutations on one putative ETS Materials and methods site failed to respond to ETV2 (Fig. 2c). The results were Complete materials and methods are presented in further corroborated by chromatin immunoprecipitation Additional file 1: Supplemental materials and methods. (ChIP)-PCR assay, confirming in vivo occupancy of ETV2 in Egfl7 promoter (Fig. 2d). Taken together, we Results conclude that the expression of Egfl7 and thus miR-126 Analysis of ETV2-mediated miRNAs is directly regulated by ETV2 in differentiating mESCs. To gain a novel insight into the molecular mechanisms of ETV2 function in FLK1+ cell generation, we performed The miR-126/MAPK pathway plays an important role for miRNA profiling analysis. FLK1+ cells from doxycycline ETV2-induced FLK1+ cell generation (Dox)-inducible ETV2 in mESC (herein, iFLAG-ETV2 MiR-126 (especially, miR-126-3p) can regulate the ESCs) [14]atday3.5ofdifferentiation±DoxwereFACS MAPK pathway through the suppression of the SPRED1 (fluorescence-activated cell sorting)-sorted and subjected to expression, a negative regulator of the MAPK pathway miRNA sequencing (Fig. 1a). The miRNAs with ≥ 1.5 fold [15, 19]. Together with the report that treatment of change and a false discovery rate (FDR) ≤ 0.05 were consid- bFGF (basic fibroblast growth factor), an agonist of FGF ered to be significantly differentially expressed, resulting in receptor-mediated signaling including MAPK [20], in- a total of 67 miRNAs of interest that were subsequently creases the generation of the FLK1+ cells from mESCs subjected to unsupervised hierarchical clustering (Fig. 1b, [21], we hypothesized that ETV2 induces FLK1+ cells c). GO (gene ontology) term analysis indicated that the partly through the miR-126-MAPK pathway by sup- ETV2-mediated miRNAs could be involved in diverse bio- pressing the expression of SPRED1. As shown in Fig. 3a logical events with embryo development, cell differentiation and b, while SPRED1 (sprouty related EVH1 domain and anatomical structure development being top ranked containing 1) was significantly reduced in response to (Fig. 1d). Signaling pathways such as MAPK, RAP1 (ras-as- ETV2, augmented phospho-ERK1/2 (extracellular signal- sociated protein 1) and WNT (wingless-related integration regulated kinases 1/2) level was evident upon the ETV2 site) were identified as the major regulatory network of the overexpression in differentiating mESCs. Interestingly, − − miRNAs, all of which are critical for cardiovascular devel- Etv2 / ESCs showed an increased level of SPRED1 ex- opment (Additional file 2: Tables S1 and S2). Some of the pression with concomitant decrease of phosphorylated differentially expressed miRNAs were validated by qRT- ERK1/2. Further, we found that ETV2-induced FLK1+ PCR (Fig. 1e and Additional file 3:FigureS1). cell generation was significantly reduced in the presence Among the differentially regulated miRNAs, miRNA- of U0126, a MAPK inhibitor,
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